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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ACTOS safely and effectively. See full prescribing information for
ACTOS.
ACTOS (pioglitazone) tablets for oral use
Initial U.S. Approval: 1999
WARNING: CONGESTIVE HEART FAILURE
See full prescribing information for complete boxed warning.
• Thiazolidinediones, including ACTOS, cause or exacerbate
congestive heart failure in some patients. (5.1)
•
After initiation of ACTOS, and after dose increases, monitor
patients carefully for signs and symptoms of heart failure
(e.g., excessive, rapid weight gain, dyspnea, and/or edema).
If heart failure develops, it should be managed according to
current standards of care and discontinuation or dose
reduction of ACTOS must be considered. (5.1)
•
ACTOS is not recommended in patients with symptomatic
heart failure. (5.1)
•
Initiation of ACTOS in patients with established New York
Heart Association (NYHA) Class III or IV heart failure is
contraindicated. (4, 5.1)
---------------------------INDICATIONS AND USAGE----------------------------ACTOS is a thiazolidinedione and an agonist for peroxisome
proliferator-activated receptor (PPAR) gamma indicated as an adjunct
to diet and exercise to improve glycemic control in adults with type 2
diabetes mellitus in multiple clinical settings. (1, 14)
Important Limitations of Use:
• Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1)
-----------------------DOSAGE AND ADMINISTRATION----------------------• Initiate ACTOS at 15 mg or 30 mg once daily. Limit initial dose to
15 mg once daily in patients with NYHA Class I or II heart failure.
(2.1)
•
If there is inadequate glycemic control, the dose can be increased
in 15 mg increments up to a maximum of 45 mg once daily. (2.1)
•
Obtain liver tests before starting ACTOS. If abnormal, use caution
when treating with ACTOS, investigate the probable cause, treat (if
possible) and follow appropriately. Monitoring liver tests while on
ACTOS is not recommended in patients without liver disease. (5.3)
-------------------------WARNINGS AND PRECAUTIONS---------------------• Congestive heart failure: Fluid retention may occur and can
exacerbate or lead to congestive heart failure. Combination use
with insulin and use in congestive heart failure NYHA Class I and II
may increase risk. Monitor patients for signs and symptoms. (5.1)
•
Hypoglycemia: When used with insulin or an insulin secretagogue,
a lower dose of the insulin or insulin secretagogue may be needed
to reduce the risk of hypoglycemia. (5.2)
•
Hepatic effects: Postmarketing reports of hepatic failure, sometimes
fatal. Causality cannot be excluded. If liver injury is detected,
promptly interrupt ACTOS and assess patient for probable cause,
then treat cause if possible, to resolution or stabilization. Do not
restart ACTOS if liver injury is confirmed and no alternate etiology
can be found. (5.3)
•
Bladder cancer: Preclinical and clinical trial data, and results from
an observational study suggest an increased risk of bladder cancer
in pioglitazone users. The observational data further suggest that
the risk increases with duration of use. Do not use in patients with
active bladder cancer. Use caution when using in patients with a
prior history of bladder cancer (5.4)
•
Edema: Dose-related edema may occur. (5.5)
•
Fractures: Increased incidence in female patients. Apply current
standards of care for assessing and maintaining bone health. (5.6)
•
Macular edema: Postmarketing reports. Recommend regular eye
exams in all patients with diabetes according to current standards
of care with prompt evaluation for acute visual changes. (5.7)
•
Macrovascular outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction
with ACTOS or any other antidiabetic drug. (5.9)
--------------------------------ADVERSE REACTIONS----------------------------Most common adverse reactions (≥5%) are upper respiratory tract
infection, headache, sinusitis, myalgia, and pharyngitis. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Takeda
Pharmaceuticals at 1-877-825-3327 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
----------------------------------DRUG INTERACTIONS---------------------------•
Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone
concentrations. Limit ACTOS dose to 15 mg daily. (2.3, 7.1)
•
----------------------DOSAGE FORMS AND STRENGTHS--------------------Tablets: 15 mg, 30 mg, and 45 mg (3)
------------------------------CONTRAINDICATIONS-------------------------------• Initiation in patients with established New York Heart Association
(NYHA) Class III or IV heart failure [see Boxed Warning]. (4)
•
Use in patients with known hypersensitivity to pioglitazone or any
other component of ACTOS. (4)
CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone
concentrations. (7.2)
-------------------------USE IN SPECIFIC POPULATIONS---------------------•
Nursing mothers: Discontinue drug or nursing, taking into
consideration the importance of the drug to the mother (8.3)
•
Pediatrics: Not recommended for use in pediatric patients. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and
Medication Guide
Revised: 11/2013
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: CONGESTIVE HEART FAILURE
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
2.1 Recommendations for All Patients
2.2 Concomitant Use with an Insulin Secretagogue or Insulin
2.3 Concomitant Use with Strong CYP2C8 Inhibitors
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Congestive Heart Failure
5.2 Hypoglycemia
5.3 Hepatic Effects
5.4 Urinary Bladder Tumors
5.5 Edema
5.6 Fractures
5.7 Macular Edema
5.8 Ovulation
5.9 Macrovascular Outcomes
6
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7
DRUG INTERACTIONS
7.1 Strong CYP2C8 Inhibitors
8
10
11
12
13
14
16
17
7.2 CYP2C8 Inducers
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
CLINICAL STUDIES
14.1 Monotherapy
14.2 Combination Therapy
HOW SUPPLIED/ STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information
are not listed.
Page 3 of 42
FULL PRESCRIBING INFORMATION
WARNING: CONGESTIVE HEART FAILURE
•
•
•
•
1
Thiazolidinediones, including ACTOS, cause or exacerbate congestive
heart failure in some patients [see Warnings and Precautions (5.1)].
After initiation of ACTOS, and after dose increases, monitor patients
carefully for signs and symptoms of heart failure (e.g., excessive, rapid
weight gain, dyspnea, and/or edema). If heart failure develops, it should be
managed according to current standards of care and discontinuation or
dose reduction of ACTOS must be considered.
ACTOS is not recommended in patients with symptomatic heart failure.
Initiation of ACTOS in patients with established New York Heart
Association (NYHA) Class III or IV heart failure is contraindicated [see
Contraindications (4) and Warnings and Precautions (5.1)].
INDICATIONS AND USAGE
Monotherapy and Combination Therapy
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies
(14)].
Important Limitations of Use
ACTOS exerts its antihyperglycemic effect only in the presence of endogenous insulin.
ACTOS should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would
not be effective in these settings.
Use caution in patients with liver disease [see Warnings and Precautions (5.3)].
2
DOSAGE AND ADMINISTRATION
2.1 Recommendations for All Patients
ACTOS should be taken once daily and can be taken without regard to meals.
The recommended starting dose for patients without congestive heart failure is 15 mg or
30 mg once daily.
The recommended starting dose for patients with congestive heart failure (NYHA Class
I or II) is 15 mg once daily.
The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily
based on glycemic response as determined by HbA1c.
After initiation of ACTOS or with dose increase, monitor patients carefully for adverse
reactions related to fluid retention such as weight gain, edema, and signs and
symptoms of congestive heart failure [see Boxed Warning and Warnings and
Precautions (5.5)].
Page 4 of 42
Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and
total bilirubin) should be obtained prior to initiating ACTOS. Routine periodic monitoring
of liver tests during treatment with ACTOS is not recommended in patients without liver
disease. Patients who have liver test abnormalities prior to initiation of ACTOS or who
are found to have abnormal liver tests while taking ACTOS should be managed as
described under Warnings and Precautions [see Warnings and Precautions (5.3) and
Clinical Pharmacology (12.3)].
2.2 Concomitant Use with an Insulin Secretagogue or Insulin
If hypoglycemia occurs in a patient co-administered ACTOS and an insulin
secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be
reduced.
If hypoglycemia occurs in a patient co-administered ACTOS and insulin, the dose of
insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose
should be individualized based on glycemic response.
2.3 Concomitant Use with Strong CYP2C8 Inhibitors
Coadministration of ACTOS and gemfibrozil, a strong CYP2C8 inhibitor, increases
pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended
dose of ACTOS is 15 mg daily when used in combination with gemfibrozil or other
strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology
(12.3)].
3
DOSAGE FORMS AND STRENGTHS
Round tablet contains pioglitazone as follows:
• 15 mg: White to off-white, debossed with “ACTOS” on one side and “15” on the other
• 30 mg: White to off-white, debossed with “ACTOS” on one side and “30” on the other
• 45 mg: White to off-white, debossed with “ACTOS” on one side and “45” on the other
4
5
CONTRAINDICATIONS
•
Initiation in patients with established NYHA Class III or IV heart failure [see
Boxed Warning].
•
Use in patients with known hypersensitivity to pioglitazone or any other
component of ACTOS.
WARNINGS AND PRECAUTIONS
5.1 Congestive Heart Failure
ACTOS, like other thiazolidinediones, can cause dose-related fluid retention when used
alone or in combination with other antidiabetic medications and is most common when
ACTOS is used in combination with insulin. Fluid retention may lead to or exacerbate
congestive heart failure. Patients should be observed for signs and symptoms of
congestive heart failure. If congestive heart failure develops, it should be managed
according to current standards of care and discontinuation or dose reduction of ACTOS
must be considered [see Boxed Warning, Contraindications (4), and Adverse Reactions
(6.1)].
Page 5 of 42
5.2 Hypoglycemia
Patients receiving ACTOS in combination with insulin or other antidiabetic medications
(particularly insulin secretagogues such as sulfonylureas) may be at risk for
hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may
be necessary to reduce the risk of hypoglycemia [see Dosage and Administration (2.2)].
5.3 Hepatic Effects
There have been postmarketing reports of fatal and non-fatal hepatic failure in patients
taking ACTOS, although the reports contain insufficient information necessary to
establish the probable cause. There has been no evidence of drug-induced
hepatotoxicity in the ACTOS controlled clinical trial database to date [see Adverse
Reactions (6.1)].
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with
episodic congestive heart failure, both of which may cause liver test abnormalities, and
they may also have other forms of liver disease, many of which can be treated or
managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase
[ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and
assessing the patient is recommended before initiating ACTOS therapy. In patients with
abnormal liver tests, ACTOS should be initiated with caution.
Measure liver tests promptly in patients who report symptoms that may indicate liver
injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or
jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT
greater than 3 times the upper limit of the reference range), ACTOS treatment should
be interrupted and investigation done to establish the probable cause. ACTOS should
not be restarted in these patients without another explanation for the liver test
abnormalities.
Patients who have serum ALT greater than three times the reference range with serum
total bilirubin greater than two times the reference range without alternative etiologies
are at risk for severe drug-induced liver injury, and should not be restarted on ACTOS.
For patients with lesser elevations of serum ALT or bilirubin and with an alternate
probable cause, treatment with ACTOS can be used with caution.
5.4 Urinary Bladder Tumors
Tumors were observed in the urinary bladder of male rats in the two-year
carcinogenicity study [see Nonclinical Toxicology (13.1)]. In two 3-year trials in which
ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of
bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not
taking ACTOS. After excluding patients in whom exposure to study drug was less than
one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on
ACTOS and two (0.05%) cases on placebo.
A five-year interim report of an ongoing 10-year observational cohort study found a nonsignificant increase in the risk for bladder cancer in subjects ever exposed to ACTOS,
compared to subjects never exposed to ACTOS (HR 1.2 [95% CI 0.9 −1.5]). Compared
to never exposure, a duration of ACTOS therapy longer than 12 months was associated
with an increase in risk (HR 1.4 [95% CI 0.9 −2.1]), which reached statistical
significance after more than 24 months of ACTOS use (HR 1.4 [95% CI 1.03 −2.0]).
Interim results from this study suggested that taking ACTOS longer than 12 months
Page 6 of 42
increased the relative risk of developing bladder cancer in any given year by 40% which
equates to an absolute increase of three cases in 10,000 (from approximately seven in
10,000 [without ACTOS] to approximately 10 in 10,000 [with ACTOS]).
There are insufficient data to determine whether pioglitazone is a tumor promoter for
urinary bladder tumors. Consequently, ACTOS should not be used in patients with
active bladder cancer and the benefits of glycemic control versus unknown risks for
cancer recurrence with ACTOS should be considered in patients with a prior history of
bladder cancer.
5.5 Edema
In controlled clinical trials, edema was reported more frequently in patients treated with
ACTOS than in placebo-treated patients and is dose-related [see Adverse Reactions
(6.1)]. In postmarketing experience, reports of new onset or worsening edema have
been received.
ACTOS should be used with caution in patients with edema. Because
thiazolidinediones, including ACTOS, can cause fluid retention, which can exacerbate or
lead to congestive heart failure, ACTOS should be used with caution in patients at risk
for congestive heart failure. Patients treated with ACTOS should be monitored for signs
and symptoms of congestive heart failure [see Boxed Warning, Warnings and
Precautions (5.1) and Patient Counseling Information (17)].
5.6 Fractures
In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events),
5238 patients with type 2 diabetes and a history of macrovascular disease were
randomized to ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633)
in addition to standard of care. During a mean follow-up of 34.5 months, the incidence
of bone fracture in females was 5.1% (44/870) for ACTOS versus 2.5% (23/905) for
placebo. This difference was noted after the first year of treatment and persisted during
the course of the study. The majority of fractures observed in female patients were
nonvertebral fractures including lower limb and distal upper limb. No increase in the
incidence of fracture was observed in men treated with ACTOS (1.7%) versus placebo
(2.1%). The risk of fracture should be considered in the care of patients, especially
female patients, treated with ACTOS and attention should be given to assessing and
maintaining bone health according to current standards of care.
5.7 Macular Edema
Macular edema has been reported in postmarketing experience in diabetic patients who
were taking ACTOS or another thiazolidinedione. Some patients presented with blurred
vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic
examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some
patients had improvement in their macular edema after discontinuation of the
thiazolidinedione.
Patients with diabetes should have regular eye exams by an ophthalmologist according
to current standards of care. Patients with diabetes who report any visual symptoms
should be promptly referred to an ophthalmologist, regardless of the patient's underlying
medications or other physical findings [see Adverse Reactions (6.1)].
Page 7 of 42
5.8 Ovulation
Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some
premenopausal anovulatory women. As a result, these patients may be at an increased
risk for pregnancy while taking ACTOS [see Use in Specific Populations (8.1)]. This
effect has not been investigated in clinical trials, so the frequency of this occurrence is
not known. Adequate contraception in all premenopausal women treated with ACTOS is
recommended.
5.9 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular
risk reduction with ACTOS or any other antidiabetic drug.
6
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
•
•
•
Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]
Edema [see Warnings and Precautions (5.5)]
Fractures [see Warnings and Precautions (5.6)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to rates in the
clinical trials of another drug and may not reflect the rates observed in practice.
Over 8500 patients with type 2 diabetes have been treated with ACTOS in randomized,
double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and
macrovascular disease treated with ACTOS in the PROactive clinical trial. In these
trials, over 6000 patients have been treated with ACTOS for six months or longer, over
4500 patients have been treated with ACTOS for one year or longer, and over 3000
patients have been treated with ACTOS for at least two years.
In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week addon combination therapy trials, the incidence of withdrawals due to adverse events was
4.5% for patients treated with ACTOS and 5.8% for comparator-treated patients. The
most common adverse events leading to withdrawal were related to inadequate
glycemic control, although the incidence of these events was lower (1.5%) with ACTOS
than with placebo (3.0%).
In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for
patients treated with ACTOS and 7.7% for placebo-treated patients. Congestive heart
failure was the most common serious adverse event leading to withdrawal occurring in
1.3% of patients treated with ACTOS and 0.6% of patients treated with placebo.
Page 8 of 42
Common Adverse Events: 16- to 26-Week Monotherapy Trials
A summary of the incidence and type of common adverse events reported in three
pooled 16- to 26-week placebo-controlled monotherapy trials of ACTOS is provided in
Table 1. Terms that are reported represent those that occurred at an incidence of >5%
and more commonly in patients treated with ACTOS than in patients who received
placebo. None of these adverse events were related to ACTOS dose.
Table 1. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of
ACTOS Monotherapy: Adverse Events Reported at an Incidence
>5% and More Commonly in Patients Treated with ACTOS than in
Patients Treated with Placebo
% of Patients
Placebo
N=259
ACTOS
N=606
Upper Respiratory Tract Infection
8.5
13.2
Headache
6.9
9.1
Sinusitis
4.6
6.3
Myalgia
2.7
5.4
Pharyngitis
0.8
5.1
Page 9 of 42
Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials
A summary of the overall incidence and types of common adverse events reported in
trials of ACTOS add-on to sulfonylurea is provided in Table 2. Terms that are reported
represent those that occurred at an incidence of >5% and more commonly with the
highest tested dose of ACTOS.
Table 2. 16- to 24-Week Clinical Trials of ACTOS Add-on to Sulfonylurea
16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More
Commonly in Patients Treated with ACTOS 30 mg
+ Sulfonylurea than in Patients Treated with Placebo
+ Sulfonylurea
% of Patients
Placebo
+ Sulfonylurea
N=187
ACTOS 15 mg
+ Sulfonylurea
N=184
ACTOS 30 mg
+ Sulfonylurea
N=189
Edema
2.1
1.6
12.7
Headache
3.7
4.3
5.3
Flatulence
0.5
2.7
6.3
0
2.7
5.3
Weight Increased
24-Week Non-Controlled Double-Blind Trial
Adverse Events Reported in >5% of Patients and More
Commonly in Patients Treated with ACTOS 45 mg
+ Sulfonylurea than in Patients Treated with ACTOS
30 mg + Sulfonylurea
% of Patients
ACTOS 30 mg
+ Sulfonylurea
N=351
ACTOS 45 mg
+ Sulfonylurea
N=351
Hypoglycemia
13.4
15.7
Edema
10.5
23.1
Upper Respiratory
Tract Infection
12.3
14.8
Weight Increased
9.1
13.4
Urinary Tract Infection
5.7
6.8
Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid
retention were combined to form the aggregate term of “edema.”
Page 10 of 42
A summary of the overall incidence and types of common adverse events reported in
trials of ACTOS add-on to metformin is provided in Table 3. Terms that are reported
represent those that occurred at an incidence of >5% and more commonly with the
highest tested dose of ACTOS.
Table 3. 16- to 24-Week Clinical Trials of ACTOS Add-on to Metformin
16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients
and More Commonly in Patients Treated with
ACTOS + Metformin than in Patients Treated
with Placebo + Metformin
% of Patients
Placebo
+ Metformin
N=160
ACTOS 30 mg
+ Metformin
N=168
Edema
2.5
6.0
Headache
1.9
6.0
24-Week Non-Controlled Double-Blind Trial
Adverse Events Reported in >5% of Patients
and More Commonly in Patients Treated with
ACTOS 45 mg + Metformin than in Patients
Treated with ACTOS 30 mg + Metformin
% of Patients
ACTOS 30 mg
+ Metformin
N=411
ACTOS 45 mg
+ Metformin
N=416
12.4
13.5
Edema
5.8
13.9
Headache
5.4
5.8
Weight Increased
2.9
6.7
Upper Respiratory Tract
Infection
Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid
retention were combined to form the aggregate term of “edema.”
Page 11 of 42
Table 4 summarizes the incidence and types of common adverse events reported in
trials of ACTOS add-on to insulin. Terms that are reported represent those that occurred
at an incidence of >5% and more commonly with the highest tested dose of ACTOS.
Table 4. 16- to 24-Week Clinical Trials of ACTOS Add-on to Insulin
16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and
More Commonly in Patients Treated with ACTOS
30 mg + Insulin than in Patients Treated with
Placebo + Insulin
Placebo
+ Insulin
N=187
% of Patients
ACTOS 15 mg
+ Insulin
N=191
ACTOS 30 mg
+ Insulin
N=188
Hypoglycemia
4.8
7.9
15.4
Edema
7.0
12.6
17.6
Upper Respiratory Tract Infection
9.6
8.4
14.9
Headache
3.2
3.1
6.9
Weight Increased
0.5
5.2
6.4
Back Pain
4.3
2.1
5.3
Dizziness
3.7
2.6
5.3
Flatulence
1.6
3.7
5.3
24-Week Non-Controlled Double-Blind Trial
Adverse Events Reported in >5% of Patients and
More Commonly in Patients Treated with
ACTOS 45 mg + Insulin than in Patients Treated
with ACTOS 30 mg + Insulin
% of Patients
ACTOS 30 mg
+ Insulin
N=345
43.5
ACTOS 45 mg
+ Insulin
N=345
47.8
22.0
26.1
Weight Increased
7.2
13.9
Urinary Tract Infection
4.9
8.7
Diarrhea
5.5
5.8
Back Pain
3.8
6.4
Blood Creatine Phosphokinase
Increased
4.6
5.5
Sinusitis
4.6
5.5
Hypertension
4.1
5.5
Hypoglycemia
Edema
Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were
combined to form the aggregate term of “edema.”
Page 12 of 42
A summary of the overall incidence and types of common adverse events reported in
the PROactive trial is provided in Table 5. Terms that are reported represent those that
occurred at an incidence of >5% and more commonly in patients treated with ACTOS
than in patients who received placebo.
Table 5. PROactive Trial: Incidence and Types of Adverse Events Reported
in >5% of Patients Treated with ACTOS and More Commonly than
Placebo
% of Patients
Placebo
N=2633
ACTOS
N=2605
Hypoglycemia
18.8
27.3
Edema
15.3
26.7
Cardiac Failure
6.1
8.1
Pain in Extremity
5.7
6.4
Back Pain
5.1
5.5
Chest Pain
5.0
5.1
Mean duration of patient follow-up was 34.5 months.
Page 13 of 42
Congestive Heart Failure
A summary of the incidence of adverse events related to congestive heart failure is
provided in Table 6 for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to
24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials.
None of the events were fatal.
Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)
Patients Treated with ACTOS or Placebo Added on to a Sulfonylurea
Number (%) of Patients
Non-Controlled
Double-Blind Trial
(24 weeks)
Placebo-Controlled Trial
(16 weeks)
At least one
congestive heart
failure event
Hospitalized
Placebo
+ Sulfonylurea
N=187
ACTOS 15 mg
+ Sulfonylurea
N=184
ACTOS 30 mg
+ Sulfonylurea
N=189
ACTOS 30 mg
+ Sulfonylurea
N=351
ACTOS 45 mg
+ Sulfonylurea
N=351
2 (1.1%)
0
0
1 (0.3%)
6 (1.7%)
2 (1.1%)
0
0
0
2 (0.6%)
Patients Treated with ACTOS or Placebo Added on to Insulin
Number (%) of Patients
Non-Controlled
Double-Blind Trial
(24 weeks)
Placebo-Controlled Trial
(16 weeks)
At least one
congestive heart
failure event
Hospitalized
Placebo
+ Insulin
N=187
ACTOS 15 mg
+ Insulin
N=191
ACTOS 30 mg
+ Insulin
N=188
ACTOS 30 mg
+ Insulin
N=345
ACTOS 45 mg
+ Insulin
N=345
0
2 (1.0%)
2 (1.1%)
3 (0.9%)
5 (1.4%)
0
2 (1.0%)
1 (0.5%)
1 (0.3%)
3 (0.9%)
Patients Treated with ACTOS or Placebo Added on to Metformin
Number (%) of Patients
Placebo-Controlled Trial
(16 weeks)
Non-Controlled
Double-Blind Trial
(24 weeks)
Placebo
+ Metformin
N=160
ACTOS 30 mg
+ Metformin
N=168
ACTOS 30 mg
+ Metformin
N=411
ACTOS 45 mg
+ Metformin
N=416
At least one
congestive heart
failure event
0
1 (0.6%)
0
1 (0.2%)
Hospitalized
0
1 (0.6%)
0
1 (0.2%)
Page 14 of 42
Patients with type 2 diabetes and NYHA class II or early class III congestive heart
failure were randomized to receive 24 weeks of double-blind treatment with either
ACTOS at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg
to 15 mg (n=256). A summary of the incidence of adverse events related to congestive
heart failure reported in this study is provided in Table 7.
Table 7. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)
in Patients with NYHA Class II or III Congestive Heart Failure Treated
with ACTOS or Glyburide
Number (%) of Subjects
ACTOS
N=262
Glyburide
N=256
5 (1.9%)
6 (2.3%)
Overnight hospitalization for worsening CHF
(adjudicated)
26 (9.9%)
12 (4.7%)
Emergency room visit for CHF (adjudicated)
4 (1.5%)
3 (1.2%)
35 (13.4%)
21 (8.2%)
Death due to cardiovascular causes (adjudicated)
Patients experiencing CHF progression during
study
Congestive heart failure events leading to hospitalization that occurred during the
PROactive trial are summarized in Table 8.
Table 8. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in
PROactive Trial
Number (%) of Patients
Placebo
N=2633
ACTOS
N=2605
108 (4.1%)
149 (5.7%)
Fatal
22 (0.8%)
25 (1.0%)
Hospitalized, nonfatal
86 (3.3%)
124 (4.7%)
At least one hospitalized congestive heart failure event
Cardiovascular Safety
In the PROactive trial, 5238 patients with type 2 diabetes and a history of
macrovascular disease were randomized to ACTOS (N=2605), force-titrated up to
45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients
(95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors,
angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin,
statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration
of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5
months.
The primary objective of this trial was to examine the effect of ACTOS on mortality and
macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk
for macrovascular events. The primary efficacy variable was the time to the first
occurrence of any event in a cardiovascular composite endpoint that included all-cause
mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary
Page 15 of 42
syndrome, cardiac intervention including coronary artery bypass grafting or
percutaneous intervention, major leg amputation above the ankle, and bypass surgery
or revascularization in the leg. A total of 514 (19.7%) patients treated with ACTOS and
572 (21.7%) placebo-treated patients experienced at least one event from the primary
composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).
Although there was no statistically significant difference between ACTOS and placebo
for the three-year incidence of a first event within this composite, there was no increase
in mortality or in total macrovascular events with ACTOS. The number of first
occurrences and total individual events contributing to the primary composite endpoint
is shown in Table 9.
Table 9. PROactive: Number of First and Total Events for Each Component within the
Cardiovascular Composite Endpoint
Placebo
N=2633
Cardiovascular Events
ACTOS
N=2605
572 (21.7)
Total
events
n
900
514 (19.7)
Total
events
n
803
122 (4.6)
186
110 (4.2)
177
Nonfatal myocardial infarction
(MI)
118 (4.5)
157
105 (4.0)
131
Stroke
96 (3.6)
119
76 (2.9)
92
Acute coronary syndrome
63 (2.4)
78
42 (1.6)
65
Cardiac intervention
(CABG/PCI)
101 (3.8)
240
101 (3.9)
195
Major leg amputation
15 (0.6)
28
9 (0.3)
28
Leg revascularization
57 (2.2)
92
71 (2.7)
115
Any event
All-cause mortality
First Events
n (%)
CABG = coronary artery bypass grafting; PCI = percutaneous intervention
First Events
n (%)
Page 16 of 42
Weight Gain
Dose-related weight gain occurs when ACTOS is used alone or in combination with
other antidiabetic medications. The mechanism of weight gain is unclear but probably
involves a combination of fluid retention and fat accumulation.
Tables 10 and 11 summarize the changes in body weight with ACTOS and placebo in
the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week
combination add-on therapy trials and in the PROactive trial.
Table 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials
Control Group
(Placebo)
Median
th
th
(25 /75
percentile)
-1.4 (-2.7/0.0)
N=256
ACTOS
15 mg
Median
th
th
(25 /75
percentile)
0.9 (-0.5/3.4)
N=79
ACTOS
30 mg
Median
th
th
(25 /75
percentile)
1.0 (-0.9/3.4)
N=188
ACTOS
45 mg
Median
th
th
(25 /75
percentile)
2.6 (0.2/5.4)
N=79
Sulfonylurea
-0.5 (-1.8/0.7)
N=187
2.0 (0.2/3.2)
N=183
3.1 (1.1/5.4)
N=528
Metformin
-1.4 (-3.2/0.3)
N=160
N/A
0.9 (-1.3/3.2)
N=567
4.1 (1.8/7.3)
N=333
1.8 (-0.9/5.0)
N=407
Insulin
0.2 (-1.4/1.4)
N=182
2.3 (0.5/4.3)
N=190
3.3 (0.9/6.3)
N=522
4.1 (1.4/6.8)
N=338
Monotherapy
(16 to 26 weeks)
Combination
Therapy
(16 to 24 weeks)
Table 11. Median Change in Body Weight in Patients Treated with ACTOS Versus Patients
Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial
Change from baseline to final visit (kg)
Placebo
ACTOS
Median
th
th
(25 /75
percentile)
Median
th
th
(25 /75
percentile)
-0.5 (-3.3, 2.0)
N=2581
Note: Median exposure for both ACTOS and Placebo was 2.7 years.
+3.6 (0.0, 7.5)
N=2560
Page 17 of 42
Edema
Edema induced from taking ACTOS is reversible when ACTOS is discontinued. The
edema usually does not require hospitalization unless there is coexisting congestive
heart failure. A summary of the frequency and types of edema adverse events occurring
in clinical investigations of ACTOS is provided in Table 12.
Table 12. Adverse Events of Edema in Patients Treated with ACTOS
Number (%) of Patients
Monotherapy (16 to 26 weeks)
Sulfonylurea
Combined Therapy
Metformin
(16 to 24 weeks)
Insulin
Placebo
ACTOS
15 mg
ACTOS
30 mg
ACTOS
45 mg
3 (1.2%)
N=259
2 (2.5%)
N= 81
13 (4.7%)
N= 275
11 (6.5%)
N=169
4 (2.1%)
N=187
3 (1.6%)
N=184
61 (11.3%)
N=540
81 (23.1%)
N=351
4 (2.5%)
N=160
N/A
34 (5.9%)
N=579
58 (13.9%)
N=416
13 (7.0%)
N=187
24 (12.6%)
N=191
109 (20.5%)
N=533
90 (26.1%)
N=345
Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid
retention were combined to form the aggregate term of “edema.”
Table 13. Adverse Events of Edema in Patients in the PROactive Trial
Number (%) of Patients
Placebo
N=2633
ACTOS
N=2605
419 (15.9%)
712 (27.3%)
Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid
retention were combined to form the aggregate term of “edema.”
Hepatic Effects
There has been no evidence of induced hepatotoxicity with ACTOS in the ACTOS
controlled clinical trial database to date. One randomized, double-blind 3-year trial
comparing ACTOS to glyburide as add-on to metformin and insulin therapy was
specifically designed to evaluate the incidence of serum ALT elevation to greater than
three times the upper limit of the reference range, measured every eight weeks for the
first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%)
patients treated with ACTOS and 9/1046 (0.9%) patients treated with glyburide
developed ALT values greater than three times the upper limit of the reference range.
None of the patients treated with ACTOS in the ACTOS controlled clinical trial database
to date have had a serum ALT greater than three times the upper limit of the reference
range and a corresponding total bilirubin greater than two times the upper limit of the
Page 18 of 42
reference range, a combination predictive of the potential for severe drug-induced liver
injury.
Hypoglycemia
In the ACTOS clinical trials, adverse events of hypoglycemia were reported based on
clinical judgment of the investigators and did not require confirmation with fingerstick
glucose testing.
In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was
3.7% with ACTOS 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial,
the incidence of reported hypoglycemia was 7.9% with ACTOS 15 mg, 15.4% with
ACTOS 30 mg, and 4.8% with placebo.
The incidence of reported hypoglycemia was higher with ACTOS 45 mg compared to
ACTOS 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and
in the 24-week add-on to insulin trial (47.8% vs. 43.5%).
Three patients in these four trials were hospitalized due to hypoglycemia. All three
patients were receiving ACTOS 30 mg (0.9%) in the 24-week add-on to insulin trial. An
additional 14 patients reported severe hypoglycemia (defined as causing considerable
interference with patient’s usual activities) that did not require hospitalization. These
patients were receiving ACTOS 45 mg in combination with sulfonylurea (n=2) or ACTOS
30 mg or 45 mg in combination with insulin (n=12).
Urinary Bladder Tumors
Tumors were observed in the urinary bladder of male rats in the two-year
carcinogenicity study [see Nonclinical Toxicology (13.1)]. In two 3-year trials in which
ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of
bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not
taking ACTOS. After excluding patients in whom exposure to study drug was less than
one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on
ACTOS and two (0.05%) cases on placebo. There are too few events of bladder cancer
to establish causality.
Laboratory Abnormalities
Hematologic Effects
ACTOS may cause decreases in hemoglobin and hematocrit. In placebo-controlled
monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated
with ACTOS compared with a mean change in hemoglobin of -1% to +1% in placebotreated patients. These changes primarily occurred within the first 4 to 12 weeks of
therapy and remained relatively constant thereafter. These changes may be related to
increased plasma volume associated with ACTOS therapy and are not likely to be
associated with any clinically significant hematologic effects.
Creatine Phosphokinase
During protocol-specified measurement of serum creatine phosphokinase (CPK) in
ACTOS clinical trials, an isolated elevation in CPK to greater than 10 times the upper
limit of the reference range was noted in nine (0.2%) patients treated with ACTOS
(values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine
patients continued to receive ACTOS, two patients were noted to have the CPK
elevation on the last day of dosing and one patient discontinued ACTOS due to the
Page 19 of 42
elevation. These elevations resolved without any apparent clinical sequelae. The
relationship of these events to ACTOS therapy is unknown.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
ACTOS. Because these reactions are reported voluntarily from a population of uncertain
size, it is generally not possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
•
•
New onset or worsening diabetic macular edema with decreased visual acuity [see
Warnings and Precautions (5.7)].
Fatal and nonfatal hepatic failure [see Warnings and Precautions (5.3)].
Postmarketing reports of congestive heart failure have been reported in patients treated
with ACTOS, both with and without previously known heart disease and both with and
without concomitant insulin administration.
In postmarketing experience, there have been reports of unusually rapid increases in
weight and increases in excess of that generally observed in clinical trials. Patients who
experience such increases should be assessed for fluid accumulation and volumerelated events such as excessive edema and congestive heart failure [see Boxed
Warning and Warnings and Precautions (5.1)].
7
DRUG INTERACTIONS
7.1 Strong CYP2C8 Inhibitors
An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area
under the serum concentration-time curve or AUC) and half-life (t½) of pioglitazone.
Therefore, the maximum recommended dose of ACTOS is 15 mg daily if used in
combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and
Administration (2.3) and Clinical Pharmacology (12.3)].
7.2 CYP2C8 Inducers
An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC)
of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during
treatment with ACTOS, changes in diabetes treatment may be needed based on clinical
response without exceeding the maximum recommended daily dose of 45 mg for
ACTOS [see Clinical Pharmacology (12.3)].
8
8.1
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C.
There are no adequate and well-controlled studies of ACTOS in pregnant women.
Animal studies show increased rates of post-implantation loss, delayed development,
reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum
recommended human dose. ACTOS should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Clinical Considerations
Abnormal blood glucose concentrations during pregnancy are associated with a higher
incidence of congenital anomalies, as well as increased neonatal morbidity and
Page 20 of 42
mortality. Most experts recommend the use of insulin during pregnancy to maintain
blood glucose concentrations as close to normal as possible for patients with diabetes.
Animal Data
In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses
up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human
oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was
observed. Increases in embryotoxicity (increased postimplantation losses, delayed
development, reduced fetal weights, and delayed parturition) occurred in rats that
received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No
functional or behavioral toxicity was observed in rat offspring. When pregnant rats
received pioglitazone during late gestation and lactation, delayed postnatal
development, attributed to decreased body weight, occurred in rat offspring at oral
maternal doses approximately two or more times the MRHD (mg/m2 basis). In rabbits,
embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).
8.3 Nursing Mothers
It is not known whether ACTOS is secreted in human milk. Pioglitazone is secreted in
the milk of lactating rats. Because many drugs are excreted in human milk, and
because of the potential for ACTOS to cause serious adverse reactions in nursing
infants, a decision should be made to discontinue nursing or discontinue ACTOS, taking
into account the importance of ACTOS to the mother.
8.4 Pediatric Use
Safety and effectiveness of ACTOS in pediatric patients have not been established.
ACTOS is not recommended for use in pediatric patients based on adverse effects
observed in adults, including fluid retention and congestive heart failure, fractures, and
urinary bladder tumors [see Warnings and Precautions (5.1, 5.4, 5.5 and 5.6)].
8.5 Geriatric Use
A total of 92 patients (15.2%) treated with ACTOS in the three pooled 16- to 26-week
double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two
patients (0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to
sulfonylurea trials, 201 patients (18.7%) treated with ACTOS were ≥65 years old and 19
(1.8%) were ≥75 years old. In the two pooled 16- to 24-week add-on to metformin trials,
155 patients (15.5%) treated with ACTOS were ≥65 years old and 19 (1.9%) were ≥75
years old. In the two pooled 16- to 24-week add-on to insulin trials, 272 patients (25.4%)
treated with ACTOS were ≥65 years old and 22 (2.1%) were ≥75 years old.
In PROactive, 1068 patients (41.0%) treated with ACTOS were ≥65 years old and 42
(1.6%) were ≥75 years old.
In pharmacokinetic studies with pioglitazone, no significant differences were observed in
pharmacokinetic parameters between elderly and younger patients [see Clinical
Pharmacology (12.3)].
Although clinical experiences have not identified differences in effectiveness and safety
between the elderly (≥65 years) and younger patients, these conclusions are limited by
small sample sizes for patients ≥75 years old.
Page 21 of 42
10
OVERDOSAGE
During controlled clinical trials, one case of overdose with ACTOS was reported. A male
patient took 120 mg per day for four days, then 180 mg per day for seven days. The
patient denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated
according to the patient’s clinical signs and symptoms.
11
DESCRIPTION
ACTOS tablets are a thiazolidinedione and an agonist for peroxisome proliferatoractivated receptor (PPAR) gamma that contains an oral antidiabetic medication:
pioglitazone.
Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-]
thiazolidinedione monohydrochloride contains one asymmetric carbon, and the
compound is synthesized and used as the racemic mixture. The two enantiomers of
pioglitazone interconvert in vivo. No differences were found in the pharmacologic
activity between the two enantiomers. The structural formula is as shown:
S
C H3
O
N
•
HCl
NH
O
O
Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular
formula of C19H20N2O3S•HCl and a molecular weight of 392.90 daltons. It is soluble in
N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in
acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or
45 mg of pioglitazone (as the base) formulated with the following excipients: lactose
monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and
magnesium stearate NF.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ACTOS is a thiazolidinedione that depends on the presence of insulin for its mechanism
of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting
in increased insulin-dependent glucose disposal and decreased hepatic glucose output.
Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome
proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues
important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation
of PPARγ nuclear receptors modulates the transcription of a number of insulin
responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, pioglitazone reduces the hyperglycemia,
hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such
as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased
Page 22 of 42
responsiveness of insulin-dependent tissues and are observed in numerous animal
models of insulin resistance.
Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin
resistance), it does not lower blood glucose in animal models that lack endogenous
insulin.
12.2
Pharmacodynamics
Clinical studies demonstrate that ACTOS improves insulin sensitivity in insulin-resistant
patients. ACTOS enhances cellular responsiveness to insulin, increases insulindependent glucose disposal and improves hepatic sensitivity to insulin. In patients with
type 2 diabetes, the decreased insulin resistance produced by ACTOS results in lower
plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c
values. In controlled clinical trials, ACTOS had an additive effect on glycemic control
when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies
(14.2)].
Patients with lipid abnormalities were included in clinical trials with ACTOS. Overall,
patients treated with ACTOS had mean decreases in serum triglycerides, mean
increases in HDL cholesterol, and no consistent mean changes in LDL and total
cholesterol. There is no conclusive evidence of macrovascular benefit with ACTOS or
any other antidiabetic medication [see Warnings and Precautions (5.9) and Adverse
Reactions (6.1)].
In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum
triglycerides decreased in the 15 mg, 30 mg, and 45 mg ACTOS dose groups compared
to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater
extent in patients treated with ACTOS than in the placebo-treated patients. There were
no consistent differences for LDL and total cholesterol in patients treated with ACTOS
compared to placebo (see Table 14).
Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study
Triglycerides (mg/dL)
Baseline (mean)
Placebo
ACTOS
15 mg
Once
Daily
ACTOS
30 mg
Once
Daily
ACTOS
45 mg
Once
Daily
N=79
N=79
N=84
N=77
263
284
261
260
†
4.8%
-9.0%
HDL Cholesterol (mg/dL)
N=79
N=79
N=83
N=77
42
40
41
41
Percent change from baseline (adjusted mean*)
8.1%
14.1%
12.2%
19.1%
LDL Cholesterol (mg/dL)
N=65
N=63
N=74
N=62
139
132
136
127
Percent change from baseline (adjusted mean*)
4.8%
7.2%
5.2%
6.0%
Total Cholesterol (mg/dL)
N=79
N=79
N=84
N=77
Baseline (mean)
†
-9.3%
†
Percent change from baseline (adjusted mean*)
Baseline (mean)
-9.6%
†
†
Page 23 of 42
Baseline (mean)
Percent change from baseline (adjusted mean*)
225
220
223
214
4.4%
4.6%
3.3%
6.4%
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p<0.05 versus placebo
In the two other monotherapy studies (16 weeks and 24 weeks) and in combination
therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and
24 weeks) or insulin (16 weeks and 24 weeks), the results were generally consistent
with the data above.
12.3 Pharmacokinetics
Following once-daily administration of ACTOS, steady-state serum concentrations of
both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone)
and M-IV (hydroxyl derivative of pioglitazone), are achieved within seven days. At
steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of
pioglitazone. At steady-state, in both healthy volunteers and patients with type 2
diabetes, pioglitazone comprises approximately 30% to 50% of the peak total
pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to
25% of the total AUC.
Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV,
increased proportionally with administered doses of 15 mg and 30 mg per day.
Absorption
Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours.
Food delays the Tmax to three to four hours but does not alter the extent of absorption
(AUC).
Distribution
The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose
administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is
extensively protein bound (>99%) in human serum, principally to serum albumin.
Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV
are also extensively bound (>98%) to serum albumin.
Metabolism
Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites
also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are
the major circulating active metabolites in humans.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of
pioglitazone, which include CYP2C8 and, to a lesser degree, CYP3A4 with additional
contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1.
In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor,
showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.3)
and Drug Interactions (7)]. Urinary 6ß-hydroxycortisol/cortisol ratios measured in
patients treated with ACTOS showed that pioglitazone is not a strong CYP3A4 enzyme
inducer.
Page 24 of 42
Excretion and Elimination
Following oral administration, approximately 15% to 30% of the pioglitazone dose is
recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is
excreted primarily as metabolites and their conjugates. It is presumed that most of the
oral dose is excreted into the bile either unchanged or as metabolites and eliminated in
the feces.
The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range
from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an
apparent clearance, CL/F, calculated to be five to seven L/hr.
Renal Impairment
The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in
patients with moderate (creatinine clearance [CLcr] 30 to 50 mL/min) and severe (CLcr
<30 mL/min) renal impairment when compared to subjects with normal renal function.
Therefore, no dose adjustment in patients with renal impairment is required.
Hepatic Impairment
Compared with healthy controls, subjects with impaired hepatic function (Child-TurcottePugh Grade B/C) have an approximate 45% reduction in pioglitazone and total
pioglitazone (pioglitazone, M-III, and M-IV) mean Cmax but no change in the mean AUC
values. Therefore, no dose adjustment in patients with hepatic impairment is required.
There are postmarketing reports of liver failure with ACTOS and clinical trials have
generally excluded patients with serum ALT >2.5 times the upper limit of the reference
range. Use caution in patients with liver disease [see Warnings and Precautions (5.3)].
Geriatric Patients
In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC
values were approximately 21% higher than those achieved in younger subjects. The
mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as
compared to younger subjects (about seven hours). These changes were not of a
magnitude that would be considered clinically relevant.
Pediatric Patients
Safety and efficacy of pioglitazone in pediatric patients have not been established.
ACTOS is not recommended for use in pediatric patients [see Use in Specific
Populations (8.4)].
Gender
The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women
compared to men. In controlled clinical trials, HbA1c decreases from baseline were
generally greater for females than for males (average mean difference in HbA1c 0.5%).
Because therapy should be individualized for each patient to achieve glycemic control,
no dose adjustment is recommended based on gender alone.
Ethnicity
Pharmacokinetic data among various ethnic groups are not available.
Page 25 of 42
Drug-Drug Interactions
Table 15. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs
Coadministered Drug
Pioglitazone
Dosage
Regimen
*
(mg)
Name and Dose Regimens
Change
†
in Cmax
Change
†
in AUC
‡
45 mg
(N = 12)
45 mg
(N = 12)
45 mg daily
for 21 days
(N = 35)
Warfarin
Daily loading then maintenance doses
based PT and INR values
Quick's Value = 35 ± 5%
Digoxin
R-Warfarin
↓3%
R-Warfarin
↓2%
S-Warfarin
↓1%
S-Warfarin
↑1%
0.200 mg twice daily (loading dose) then
0.250 mg daily (maintenance dose, 7 days)
Oral Contraceptive
[Ethinyl Estradiol (EE) 0.035 mg plus
Norethindrone (NE) 1 mg] for 21 days
↑15%
↑17%
↓11%
↑3%
EE
NE
↓13%
↓7%
EE
NE
45 mg
(N = 23)
Fexofenadine
60 mg twice daily for 7 days
↑30%
↑37%
45 mg
(N = 14)
Glipizide
5 mg daily for 7 days
↓3%
↓8%
↓3%
↓5%
↓26%
↓26%
↑1%
↓1%
↓13%
↓17%
↓14%
↓23%
↑2%
↑5%
45 mg daily
for 8 days
(N = 16)
Metformin
1000 mg single dose on Day 8
45 mg
(N = 21)
Midazolam
45 mg
(N = 24)
Ranitidine
45 mg daily
for 4 days
(N = 24)
7.5 mg single dose on Day 15
150 mg twice daily for 7 days
Nifedipine ER
30 mg daily for 4 days
45 mg
(N = 25)
Atorvastatin Ca
45 mg
(N = 22)
Theophylline
80 mg daily for 7 days
400 mg twice daily for 7 days
*Daily for 7 days unless otherwise noted
†% change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure
increase and decrease, respectively
‡Pioglitazone had no clinically significant effect on prothrombin time
Page 26 of 42
Table 16. Effect of Coadministered Drugs on Pioglitazone Systemic
Exposure
Pioglitazone
Coadministered Drug and
Dosage Regimen
Dose
Regimen
(mg)*
Change
†
in AUC
Change
†
in Cmax
Gemfibrozil 600 mg
twice daily for 2 days
(N = 12)
15 mg
single dose
↑3.2-fold
↑6%
Ketoconazole 200 mg
twice daily for 7 days
(N = 28)
45 mg
↑34%
↑14%
Rifampin 600 mg
daily for 5 days
(N = 10)
30 mg
single dose
↓54%
↓5%
Fexofenadine 60 mg
twice daily for 7 days
(N = 23)
45 mg
↑1%
0%
Ranitidine 150 mg
twice daily for 4 days
(N = 23)
45 mg
↓13%
↓16%
Nifedipine ER 30 mg
daily for 7 days
(N = 23)
45 mg
↑5%
↑4%
Atorvastatin Ca 80 mg
daily for 7 days
(N = 24)
45 mg
↓24%
↓31%
Theophylline 400 mg
twice daily for 7 days
(N = 22)
45 mg
↓4%
↓2%
‡
*Daily for 7 days unless otherwise noted
†Mean ratio (with/without coadministered drug and no change = 1-fold) % change
(with/without coadministered drug and no change = 0%); symbols of ↑ and ↓
indicate the exposure increase and decrease, respectively
‡The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence
of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7)]
Page 27 of 42
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in male and female rats at oral doses
up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose
of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ
except for the urinary bladder of male rats. Benign and/or malignant transitional cell
neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal
to the maximum recommended human oral dose based on mg/m2). Urinary calculi with
subsequent irritation and hyperplasia were postulated as the mechanism for bladder
tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary
acidification to reduce calculi formation was completed in 2009. Dietary acidification
decreased but did not abolish the hyperplastic changes in the bladder. The presence of
calculi exacerbated the hyperplastic response to pioglitazone but was not considered
the primary cause of the hyperplastic changes.
The relevance to humans of the bladder findings in the male rat cannot be excluded.
A two-year carcinogenicity study was also conducted in male and female mice at oral
doses up to 100 mg/kg/day (approximately 11 times the maximum recommended
human oral dose based on mg/m2). No drug-induced tumors were observed in any
organ.
Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies,
including the Ames bacterial assay, a mammalian cell forward gene mutation assay
(CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an
unscheduled DNA synthesis assay, and an in vivo micronucleus assay.
No adverse effects upon fertility were observed in male and female rats at oral doses up
to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and
gestation (approximately nine times the maximum recommended human oral dose
based on mg/m2).
13.2 Animal Toxicology and/or Pharmacology
Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above)
and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1,
and 2 times the maximum recommended human oral dose for mice, rats, and dogs,
respectively, based on mg/m2). In a one-year rat study, drug-related early death due to
apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately
35 times the maximum recommended human oral dose based on mg/m2). Heart
enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and
above (approximately four times the maximum recommended human oral dose based
on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13
times the maximum recommended human oral dose based on mg/m2).
14
CLINICAL STUDIES
14.1 Monotherapy
Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26
weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with
Page 28 of 42
type 2 diabetes. These trials examined ACTOS at doses up to 45 mg or placebo once
daily in a total of 865 patients.
In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were
randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once
daily. Therapy with any previous antidiabetic agent was discontinued eight weeks prior
to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS
produced statistically significant improvements in HbA1c and fasting plasma glucose
(FPG) at endpoint compared to placebo (see Figure 1, Table 17).
Figure 1 shows the time course for changes in HbA1c in this 26-week study.
Figure 1.
Mean Change from Baseline for HbA1c in a 26-Week Placebo-Controlled DoseRanging Study (Observed Values)
1.0
0.5
Mean
0.0
-0.5
-1.0
-1.5
-2.0
0
2
4
6
Placebo
10
14
Weeks
15 mg
30 mg
18
45 mg
22
26
Page 29 of 42
Table 17. Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging
Monotherapy Trial
Placebo
ACTOS
15 mg
Once
Daily
ACTOS
30 mg
Once
Daily
ACTOS
45 mg
Once
Daily
HbA1c (%)
N=79
N=79
N=85
N=76
Baseline (mean)
10.4
10.2
10.2
10.3
Change from baseline (adjusted mean*)
0.7
-0.3
-0.3
-0.9
†
†
Total Population
Fasting Plasma Glucose (mg/dL)
Baseline (mean)
Change from baseline (adjusted mean*)
Difference from placebo (adjusted mean*)
95% Confidence Interval
†
-1.0
(-1.6, -0.4)
-1.0
(-1.6, -0.4)
-1.6
(-2.2, -1.0)
N=79
N=79
N=84
N=77
268
267
269
276
9
-30
-32
-56
Difference from placebo (adjusted mean*)
95% Confidence Interval
†
-39
(-63, -16)
†
-41
(-64, -18)
†
-65
(-89, -42)
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.05 vs. placebo
In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes
were randomized to one of two forced-titration ACTOS treatment groups or a mocktitration placebo group. Therapy with any previous antidiabetic agent was discontinued
six weeks prior to the double-blind period. In one ACTOS treatment group, patients
received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased
to 15 mg once daily and after another four weeks, the dose was increased to 30 mg
once daily for the remainder of the trial (16 weeks). In the second ACTOS treatment
group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg
once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as
described, produced statistically significant improvements in HbA1c and FPG at
endpoint compared to placebo (see Table 18).
Page 30 of 42
Table 18. Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration
Monotherapy Trial
Placebo
ACTOS
30 mg*
Once Daily
ACTOS
45 mg*
Once Daily
HbA1c (%)
N=83
N=85
N=85
Baseline (mean)
10.8
10.3
10.8
0.9
-0.6
-0.6
Total Population
†
Change from baseline (adjusted mean )
†
‡
Fasting Plasma Glucose (mg/dL)
Baseline (mean)
†
Change from baseline (adjusted mean )
†
Difference from placebo (adjusted mean )
95% Confidence Interval
‡
-1.5
(-2.0, -1.0)
-1.5
(-2.0, -1.0)
N=78
N=82
N=85
279
268
281
18
-44
-50
Difference from placebo (adjusted mean )
95% Confidence Interval
‡
-62
(-82, -0.41)
‡
-68
(-88, -0.48)
*Final dose in forced titration
†Adjusted for baseline, pooled center, and pooled center by treatment interaction
‡p≤0.05 vs. placebo
In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to
treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous
antidiabetic agent was discontinued six weeks prior to the double-blind period.
Treatment with 30 mg of ACTOS produced statistically significant improvements in
HbA1c and FPG at endpoint compared to placebo (see Table 19).
Page 31 of 42
Table 19. Glycemic Parameters in a 16-Week Placebo-Controlled Monotherapy Trial
Placebo
ACTOS 30 mg
Once Daily
HbA1c (%)
N=93
N=100
Baseline (mean)
10.3
10.5
Change from baseline (adjusted mean*)
0.8
-0.6
Total Population
†
Difference from placebo (adjusted mean*)
95% Confidence Interval
Fasting Plasma Glucose (mg/dL)
Baseline (mean)
Change from baseline (adjusted mean*)
-1.4
(-1.8, -0.9)
N=91
N=99
270
273
8
-50
Difference from placebo (adjusted mean*)
95% Confidence Interval
†
-58
(-77, -38)
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.050 vs. placebo
14.2 Combination Therapy
Three 16-week, randomized, double-blind, placebo-controlled clinical trials were
conducted to evaluate the effects of ACTOS (15 mg and/or 30 mg) on glycemic control
in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite
current therapy with a sulfonylurea, metformin, or insulin. In addition, three 24-week
randomized, double-blind clinical trials were conducted to evaluate the effects of
ACTOS 30 mg vs. ACTOS 45 mg on glycemic control in patients with type 2 diabetes
who were inadequately controlled (HbA1c ≥8%) despite current therapy with a
sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been
monotherapy or combination therapy.
Add-on to Sulfonylurea Trials
Two clinical trials were conducted with ACTOS in combination with a sulfonylurea. Both
studies included patients with type 2 diabetes on any dose of a sulfonylurea, either
alone or in combination with another antidiabetic agent. All other antidiabetic agents
were withdrawn at least three weeks prior to starting study treatment.
In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or
placebo once daily for 16 weeks in addition to their current sulfonylurea regimen.
Treatment with ACTOS as add-on to sulfonylurea produced statistically significant
improvements in HbA1c and FPG at endpoint compared to placebo add-on to
sulfonylurea (see Table 20).
Page 32 of 42
Table 20. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to
Sulfonylurea Trial
Placebo
+ Sulfonylurea
ACTOS 15 mg
+ Sulfonylurea
ACTOS 30 mg
+ Sulfonylurea
N=181
N=176
N=182
Baseline (mean)
9.9
10.0
9.9
Change from baseline (adjusted mean*)
0.1
-0.8
-1.2
Total Population
HbA1c (%)
Difference from placebo + sulfonylurea
(adjusted mean*)
95% Confidence Interval
Fasting Plasma Glucose (mg/dL)
Baseline (mean)
Change from baseline (adjusted mean*)
Difference from placebo +sulfonylurea
(adjusted mean*)
95% Confidence Interval
†
†
-0.9
(-1.2, -0.6)
-1.3
(-1.6, -1.0)
N=182
N=179
N=186
236
247
239
6
-34
-52
†
-39
(-52, -27)
†
-58
(-70, -46)
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.05 vs. placebo + sulfonylurea
In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS
once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean
reduction from baseline at Week 24 in HbA1c was 1.6% for the 30 mg dose and 1.7%
for the 45 mg dose (see Table 21). The mean reduction from baseline at Week 24 in
FPG was 52 mg/dL for the 30 mg dose and 56 mg/dL for the 45 mg dose.
The therapeutic effect of ACTOS in combination with sulfonylurea was observed in
patients regardless of the sulfonylurea dose.
Page 33 of 42
Table 21. Glycemic Parameters in a 24-Week Add-on to Sulfonylurea Trial
ACTOS 30 mg
+ Sulfonylurea
ACTOS 45 mg
+ Sulfonylurea
N=340
N=332
Baseline (mean)
9.8
9.9
Change from baseline (adjusted mean*)
-1.6
-1.7
Total Population
HbA1c (%)
Difference from 30 mg daily ACTOS
+ sulfonylurea (adjusted mean*) (95% CI)
Fasting Plasma Glucose (mg/dL)
-0.1
(-0.4, 0.1)
N=338
N=329
Baseline (mean)
214
217
Change from baseline (adjusted mean*)
-52
-56
Difference from 30 mg daily ACTOS
+ sulfonylurea (adjusted mean*) (95% CI)
-5
(-12, 3)
95% CI = 95% confidence interval
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
Add-on to Metformin Trials
Two clinical trials were conducted with ACTOS in combination with metformin. Both
trials included patients with type 2 diabetes on any dose of metformin, either alone or in
combination with another antidiabetic agent. All other antidiabetic agents were
withdrawn at least three weeks prior to starting study treatment.
In the first trial, 328 patients were randomized to receive either 30 mg of ACTOS or
placebo once daily for 16 weeks in addition to their current metformin regimen.
Treatment with ACTOS as add-on to metformin produced statistically significant
improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin
(see Table 22).
Page 34 of 42
Table 22. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to
Metformin Trial
Placebo
+ Metformin
ACTOS 30 mg
+ Metformin
N=153
N=161
Baseline (mean)
9.8
9.9
Change from baseline (adjusted mean*)
0.2
-0.6
Total Population
HbA1c (%)
†
-0.8
(-1.2, -0.5)
Difference from placebo + metformin (adjusted
mean*) 95% Confidence Interval
Fasting Plasma Glucose (mg/dL)
Baseline (mean)
Change from baseline (adjusted mean*)
Difference from placebo + metformin (adjusted
mean*) 95% Confidence Interval
N=157
N=165
260
254
-5
-43
†
-38
(-49, -26)
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.05 vs. placebo + metformin
In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of
ACTOS once daily for 24 weeks in addition to their current metformin regimen. The
mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and
1.0% for the 45 mg dose (see Table 23). The mean reduction from baseline at Week 24
in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.
Page 35 of 42
Table 23. Glycemic Parameters in a 24-Week Add-on to Metformin Study
ACTOS 30 mg
+ Metformin
ACTOS 45 mg
+ Metformin
N=400
N=398
9.9
9.8
-0.8
-1.0
Total Population
HbA1c (%)
Baseline (mean)
Change from baseline (adjusted mean*)
Difference from 30 mg daily ACTOS
+ Metformin (adjusted mean*) (95% CI)
Fasting Plasma Glucose (mg/dL)
-0.2
(-0.5, 0.1)
N=398
N=399
Baseline (mean)
233
232
Change from baseline (adjusted mean*)
-38
-51
Difference from 30 mg daily ACTOS
+ Metformin (adjusted mean*) (95% CI)
†
-12
(-21, -4)
95% CI = 95% confidence interval
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.05 vs. 30 mg daily ACTOS + metformin
The therapeutic effect of ACTOS in combination with metformin was observed in
patients regardless of the metformin dose.
Add-on to Insulin Trials
Two clinical trials were conducted with ACTOS in combination with insulin. Both trials
included patients with type 2 diabetes on insulin, either alone or in combination with
another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting
study treatment. In the first trial, 566 patients were randomized to receive either 15 mg
or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin
regimen. Treatment with ACTOS as add-on to insulin produced statistically significant
improvements in HbA1c and FPG at endpoint compared to placebo add-on to insulin
(see Table 24). The mean daily insulin dose at baseline in each treatment group was
approximately 70 units. The majority of patients (75% overall, 86% treated with placebo,
77% treated with ACTOS 15 mg, and 61% treated with ACTOS 30 mg) had no change
in their daily insulin dose from baseline to the final study visit. The mean change from
baseline in daily dose of insulin (including patients with no insulin dose modifications)
was -3 units in the patients treated with ACTOS 15 mg, -8 units in the patients treated
with ACTOS 30 mg, and -1 unit in patients treated with placebo.
Page 36 of 42
Table 24. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Insulin Trial
Placebo
+ Insulin
ACTOS 15 mg
+ Insulin
ACTOS 30 mg
+ Insulin
N=177
N=177
N=185
Baseline (mean)
9.8
9.8
9.8
Change from baseline (adjusted mean*)
-0.3
-1.0
-1.3
Total Population
HbA1c (%)
†
Fasting Plasma Glucose (mg/dL)
Baseline (mean)
Change from baseline (adjusted mean*)
Difference from placebo + Insulin (adjusted
mean*) 95% Confidence Interval
†
-0.7
(-1.0, -0.5)
-1.0
(-1.3, -0.7)
N=179
N=183
N=184
221
222
229
1
-35
-48
Difference from placebo + Insulin (adjusted
mean*) 95% Confidence Interval
†
-35
(-51, -19)
†
-49
(-65, -33)
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.05 vs. placebo + insulin
In the second trial, 690 patients receiving a median of 60 units per day of insulin were
randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in
addition to their current insulin regimen. The mean reduction from baseline at Week 24
in HbA1c was 1.2% for the 30 mg dose and 1.5% for the 45 mg dose. The mean
reduction from baseline at Week 24 in FPG was 32 mg/dL for the 30 mg dose and
46 mg/dL for the 45 mg dose (see Table 25). The mean daily insulin dose at baseline in
both treatment groups was approximately 70 units. The majority of patients (55%
overall, 58% treated with ACTOS 30 mg, and 52% treated with ACTOS 45 mg) had no
change in their daily insulin dose from baseline to the final study visit. The mean change
from baseline in daily dose of insulin (including patients with no insulin dose
modifications) was -5 units in the patients treated with ACTOS 30 mg and -8 units in the
patients treated with ACTOS 45 mg.
The therapeutic effect of ACTOS in combination with insulin was observed in patients
regardless of the insulin dose.
Page 37 of 42
Table 25. Glycemic Parameters in a 24-Week Add-on to Insulin Trial
ACTOS 30 mg
+ Insulin
ACTOS 45 mg
+ Insulin
N=328
N=328
Baseline (mean)
9.9
9.7
Change from baseline (adjusted mean*)
-1.2
-1.5
Total Population
HbA1c (%)
†
Difference from 30 mg daily ACTOS
+ Insulin (adjusted mean*) (95% CI)
Fasting Plasma Glucose (mg/dL)
-0.3
(-0.5, -0.1)
N=325
N=327
Baseline (mean)
202
199
Change from baseline (adjusted mean*)
-32
-46
Difference from 30 mg daily ACTOS
+ Insulin (adjusted mean*) (95% CI)
†
-14
(-25, -3)
95% CI = 95% confidence interval
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.05 vs. 30 mg daily ACTOS + insulin
16 HOW SUPPLIED/STORAGE AND HANDLING
ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows:
15 mg tablet: White to off-white, round, convex, nonscored tablet with “ACTOS” on one
side, and “15” on the other, available in:
NDC 64764-151-04
NDC 64764-151-05
NDC 64764-151-06
Bottles of 30
Bottles of 90
Bottles of 500
30 mg tablet: White to off-white, round, flat, nonscored tablet with “ACTOS” on one side,
and “30” on the other, available in:
NDC 64764-301-14
NDC 64764-301-15
NDC 64764-301-16
Bottles of 30
Bottles of 90
Bottles of 500
45 mg tablet: White to off-white, round, flat, nonscored tablet with “ACTOS” on one side,
and “45” on the other, available in:
NDC 64764-451-24
NDC 64764-451-25
NDC 64764-451-26
Bottles of 30
Bottles of 90
Bottles of 500
Page 38 of 42
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled
Room Temperature]. Keep container tightly closed, and protect from light, moisture and
humidity.
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Medication Guide).
•
•
•
•
•
•
•
It is important to instruct patients to adhere to dietary instructions and to have blood
glucose and glycosylated hemoglobin tested regularly. During periods of stress such
as fever, trauma, infection, or surgery, medication requirements may change and
patients should be reminded to seek medical advice promptly.
Patients who experience an unusually rapid increase in weight or edema or who
develop shortness of breath or other symptoms of heart failure while on ACTOS
should immediately report these symptoms to a physician.
Tell patients to promptly stop taking ACTOS and seek immediate medical advice if
there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark
urine as these symptoms may be due to hepatotoxicity.
Tell patients to promptly report any sign of macroscopic hematuria or other
symptoms such as dysuria or urinary urgency that develop or increase during
treatment as these may be due to bladder cancer.
Tell patients to take ACTOS once daily. ACTOS can be taken with or without meals.
If a dose is missed on one day, the dose should not be doubled the following day.
When using combination therapy with insulin or other antidiabetic medications, the
risks of hypoglycemia, its symptoms and treatment, and conditions that predispose
to its development should be explained to patients and their family members.
Inform patients that therapy with ACTOS, like other thiazolidinediones, may result in
ovulation in some premenopausal anovulatory women. As a result, these patients
may be at an increased risk for pregnancy while taking ACTOS. Therefore, adequate
contraception should be recommended for all premenopausal women who are
prescribed ACTOS.
Distributed by:
Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015
ACTOS is a trademark of Takeda Pharmaceutical Company Limited registered with the
U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals
America, Inc.
©1999 - 2013 Takeda Pharmaceuticals America, Inc.
ACT003 R20
Page 39 of 42
MEDICATION GUIDE
ACTOS (ak-TŌS)
(pioglitazone) tablets
Read this Medication Guide carefully before you start taking ACTOS and each time
you get a refill. There may be new information. This information does not take the
place of talking with your doctor about your medical condition or your treatment. If
you have any questions about ACTOS, ask your doctor or pharmacist.
What is the most important information I should know about ACTOS?
ACTOS can cause serious side effects, including new or worse heart failure.
• ACTOS can cause your body to keep extra fluid (fluid retention), which leads to
swelling (edema) and weight gain. Extra body fluid can make some heart
problems worse or lead to heart failure. Heart failure means your heart does not
pump blood well enough
• Do not take ACTOS if you have severe heart failure
• If you have heart failure with symptoms (such as shortness of breath or
swelling), even if these symptoms are not severe, ACTOS may not be right for
you
Call your doctor right away if you have any of the following:
• swelling or fluid retention, especially in the ankles or legs
• shortness of breath or trouble breathing, especially when you lie down
• an unusually fast increase in weight
• unusual tiredness
ACTOS can have other serious side effects. See “What are the possible side effects
of ACTOS?”
What is ACTOS?
ACTOS is a prescription medicine used with diet and exercise to improve blood
sugar (glucose) control in adults with type 2 diabetes. ACTOS is a diabetes
medicine called pioglitazone that may be taken alone or with other diabetes
medicines.
It is not known if ACTOS is safe and effective in children under the age of 18.
ACTOS is not recommended for use in children.
ACTOS is not for people with type 1 diabetes.
ACTOS is not for people with diabetic ketoacidosis (increased ketones in your blood
or urine).
Who should not take ACTOS?
See “What is the most important information I should know about ACTOS?”
Do not take ACTOS if you:
• have severe heart failure
• are allergic to any of the ingredients in ACTOS. See the end of this Medication
Guide for a complete list of ingredients in ACTOS
Page 40 of 42
Talk to your doctor before taking ACTOS if you have either of these conditions.
What should I tell my doctor before taking ACTOS?
Before you take ACTOS, tell your doctor if you:
• have heart failure
• have type 1 (“juvenile”) diabetes or had diabetic ketoacidosis
• have a type of diabetic eye disease that causes swelling in the back of
the eye (macular edema)
• have liver problems
• have or have had cancer of the bladder
• are pregnant or plan to become pregnant. It is not known if ACTOS will
harm your unborn baby. Talk to your doctor if you are pregnant or plan to
become pregnant about the best way to control your blood glucose levels while
pregnant
• are a premenopausal woman (before the “change of life”) who does not
have periods regularly or at all. ACTOS may increase your chance of
becoming pregnant. Talk to your doctor about birth control choices while taking
ACTOS. Tell your doctor right away if you become pregnant while taking ACTOS
• are breastfeeding or plan to breastfeed. It is not known if ACTOS passes
into your milk and if it can harm your baby. You should not take ACTOS if you
breastfeed your baby. Talk to your doctor about the best way to control your
blood glucose levels while breastfeeding
Tell your doctor about all the medicines you take including prescription and
over the counter medicines, vitamins, and herbal supplements.
ACTOS and some of your other medicines can affect each other. You may need to
have your dose of ACTOS or certain other medicines changed.
Know the medicines you take. Keep a list of your medicines and show it to your
doctor and pharmacist before you start a new medicine. They will tell you if it is
okay to take ACTOS with other medicines.
How should I take ACTOS?
• Take ACTOS exactly as your doctor tells you to take it
• Your doctor may change your dose of ACTOS. Do not change your ACTOS dose
unless your doctor tells you to
• ACTOS may be prescribed alone or with other diabetes medicines. This will
depend on how well your blood sugar is controlled
• Take ACTOS one time each day, with or without food
• If you miss a dose of ACTOS, take your next dose as prescribed unless your
doctor tells you differently. Do not take two doses at one time the next day
• If you take too much ACTOS, call your doctor or go to the nearest hospital
emergency room right away
• If your body is under stress such as from a fever, infection, accident, or surgery
the dose of your diabetes medicines may need to be changed. Call your doctor
right away
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Stay on your diet and exercise programs and test your blood sugar regularly
while taking ACTOS
Your doctor should do certain blood tests before you start and while you take
ACTOS
Your doctor should also do hemoglobin A1C testing to check how well your blood
sugar is controlled with ACTOS
Your doctor should check your eyes regularly while you take ACTOS
What are the possible side effects of ACTOS?
ACTOS may cause serious side effects including:
• See “What is the most important information I should know about
ACTOS?”
• low blood sugar (hypoglycemia). This can happen if you skip meals, if you
also use another medicine that lowers blood sugar, or if you have certain
medical problems. Lightheadedness, dizziness, shakiness, or hunger may
happen if your blood sugar is too low. Call your doctor if low blood sugar levels
are a problem for you
• liver problems. Call your doctor right away if you have:
o nausea or vomiting
o stomach pain
o unusual or unexplained tiredness
o loss of appetite
o dark urine
o yellowing of your skin or the whites of your eyes
• bladder cancer. There may be an increased chance of having bladder cancer
when you take ACTOS. You should not take ACTOS if you are receiving
treatment for bladder cancer. Tell your doctor right away if you have any of the
following symptoms of bladder cancer:
o blood or a red color in your urine
o an increased need to urinate
o pain while you urinate
• broken bones (fractures). Usually in the hand, upper arm, or foot in women.
Talk to your doctor for advice on how to keep your bones healthy.
• diabetic eye disease with swelling in the back of the eye (macular
edema). Tell your doctor right away if you have any changes in your vision.
Your doctor should check your eyes regularly
• release of an egg from an ovary in a woman (ovulation) leading to
pregnancy. Ovulation may happen when premenopausal women who do not
have regular monthly periods take ACTOS. This can increase your chance of
getting pregnant
The most common side effects of ACTOS include:
o cold-like symptoms (upper respiratory tract infection)
o headache
o sinus infection
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o muscle pain
o sore throat
Tell your doctor if you have any side effect that bothers you or that does not go
away. These are not all the side effects of ACTOS. For more information, ask your
doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store ACTOS?
• Store ACTOS at 68°F to 77°F (20°C to 25°C). Keep ACTOS in the original
container and protect from light
• Keep the ACTOS bottle tightly closed and keep tablets dry
• Keep ACTOS and all medicines out of the reach of children
General information about the safe and effective use of ACTOS
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use ACTOS for a condition for which it was not prescribed.
Do not give ACTOS to other people, even if they have the same symptoms you
have. It may harm them.
This Medication Guide summarizes the most important information about ACTOS. If
you would like more information, talk with your doctor. You can ask your doctor or
pharmacist for information about ACTOS that is written for healthcare professionals.
For more information, go to www.actos.com or call 1-877-825-3327.
What are the ingredients in ACTOS?
Active Ingredient: pioglitazone
Inactive Ingredients: lactose monohydrate, hydroxypropylcellulose,
carboxymethylcellulose calcium, and magnesium stearate
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Distributed by:
Takeda Pharmaceuticals America, Inc.
Deerfield, IL 60015
Revised: November 2013
ACTOS is a trademark of Takeda Pharmaceutical Company Limited registered with
the U.S. Patent and Trademark Office and used under license by Takeda
Pharmaceuticals America, Inc.
©2009 - 2013 Takeda Pharmaceuticals America, Inc.
ACT003 R20